Iron plays a critical role in both the healthy and diseased retina. The long term goals of the proposed studies are to understand regulation of retinal iron flux, determine why iron accumulates in retinal disease, and discover how to protect against retina iron toxicity. Iron is necessary in the retina for oxidative phosphorylation, membrane biogenesis and retinol isomerization, but becomes a central producer of oxidative stress when improperly regulated. Iron toxicity is evident in retinal disease as follows: 1) Iron causes rapid retinal degeneration following entry into the eye carried by an intraocular foreign body. 2) Human AMD retinas have more iron than age-matched controls, suggesting that iron overload may play a role in AMD pathogenesis. 3) Consistent with this hypothesis, in the inherited disease aceruloplasminemia, loss of the ferroxidase ceruloplasmin (Cp) results in retinal iron accumulation and early onset macular degeneration. 4) Mice with knockout for Cp and its homolog hephaestin (Heph) have an age-dependent retinal iron overload and degeneration sharing features of AMD, including complement activation and subretinal neovascularization. The latter two points indicate that Cp and Heph are important for retinal health. Evidence from other organs suggests that Cp or Heph can cooperate with the plasma membrane iron transporter ferroportin (Fpn) to export iron from cells. Progress from our prior funding period indicates that Heph plays a cell-autonomous role in RPE iron export, but that it also has a critical function in inner retinal iron transport. One goal of the current proposal is t discover the role of Muller cell Heph in retinal iron regulation. Another goal is to test the hypothesis that a third, recently identified ferroxidase, amyloid precursor protein (APP), mediates iron import into the retina. The balance of retinal iron importers and exporters is controlled by iron regulatory proteins (IRPs). These can be dysregulated in disease by hypoxia or oxidative stress. We will assess the role of IRPs in retinal iron regulation in healthy and diseased retinas. The synergistic proposed studies using primary cell culture, systemic and cell-type specific conditional knockouts and post mortem human tissues will increase our understanding of the effects of ferroxidases and IRPs on retinal iron in health and disease.

Public Health Relevance

The proposed work on the mechanisms of retinal iron regulation is important for protecting human health because iron dysregulation can occur with age-related macular degeneration (AMD), glaucoma, retinitis pigmentosa, and intraocular hemorrhage or foreign body, most likely exacerbating these diseases. Our knowledge of retinal iron regulation in the normal retina and understanding of the mechanism of iron accumulation in retinal disease are incomplete. The proposed studies will increase understanding of these mechanisms and provide new mouse models for testing potential therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY015240-09
Application #
8503300
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Neuhold, Lisa
Project Start
2003-11-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$581,989
Indirect Cost
$218,246
Name
University of Pennsylvania
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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He, Lizhi; Marioutina, Mariya; Dunaief, Joshua L et al. (2014) Age- and gene-dosage-dependent cre-induced abnormalities in the retinal pigment epithelium. Am J Pathol 184:1660-7
Zhao, Liangliang; Wang, Chenguang; Song, Delu et al. (2014) Systemic administration of the antioxidant/iron chelator ?-lipoic acid protects against light-induced photoreceptor degeneration in the mouse retina. Invest Ophthalmol Vis Sci 55:5979-88
Fuqua, Brie K; Lu, Yan; Darshan, Deepak et al. (2014) The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice. PLoS One 9:e98792
Wolkow, Natalie; Li, Yafeng; Maminishkis, Arvydas et al. (2014) Iron upregulates melanogenesis in cultured retinal pigment epithelial cells. Exp Eye Res 128:92-101
Song, Delu; Grieco, Steve; Li, Yafeng et al. (2014) A murine RP1 missense mutation causes protein mislocalization and slowly progressive photoreceptor degeneration. Am J Pathol 184:2721-9
Song, Delu; Zhao, Liangliang; Li, Yafeng et al. (2014) The oral iron chelator deferiprone protects against systemic iron overload-induced retinal degeneration in hepcidin knockout mice. Invest Ophthalmol Vis Sci 55:4525-32
Zhao, Chen; Yasumura, Douglas; Li, Xiyan et al. (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369-83
Iacovelli, Jared; Zhao, Chen; Wolkow, Natalie et al. (2011) Generation of Cre transgenic mice with postnatal RPE-specific ocular expression. Invest Ophthalmol Vis Sci 52:1378-83

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